Cancer refers to more than one hundred clinically distinct forms of the disease. Almost every tissue of the body can give rise to cancer and some can even yield several types of cancer. Cancer is characterized by an abnormal growth of cells which can invade the tissue of origin or spread to other sites. In fact, the seriousness of a particular cancer, or the degree of malignancy, is based upon the propensity of cancer cells for invasion and the ability to spread. That is, various human cancers (e.g., carcinomas) differ appreciably as to their ability to spread from a primary site or tumor and metastasize throughout the body. Indeed, it is the process of tumor metastasis which is detrimental to the survival of the cancer patient. A surgeon can remove a primary tumor, but a cancer that has metastasized often reaches too many places to permit a surgical cure. To successfully metastasize, cancer cells must detach from their original location, invade a blood or lymphatic vessel, travel in the circulation to a new site, and establish a tumor.
The twelve major cancers are prostate, breast, lung, colorectal, bladder, non-Hodgkin's lymphoma, uterine, melanoma, kidney, leukemia, ovarian, and pancreatic cancers. Generally, four types of treatment have been used for the treatment of metastatic cancers: surgery, radiation therapy, chemotherapy, and immunotherapy. Surgery may be used to remove the primary tumor and/or to improve the quality of life by removing a metastasis, for example, that is obstructing the gastrointestinal tract. Radiation therapy may also be used for treatment of a primary tumor where it is difficult to surgically remove the entire tumor and/or to treat cutaneous and/or lymph node metastasis. A number of chemotherapeutic drugs are available for the treatment of cancer and most often the treatment regimen calls for a combination of these drugs, primarily to deal with the phenomena of drug resistance. That is, the biochemical process which develops over time whereby the cancer is no longer responsive, or becomes refractory, to a particular chemotherapeutic drug prior to eradication of the cancer. Immunotherapy is mostly limited to the use of cytokines or therapeutic cancer vaccines. These treatments have also met with limited success. Treatment with cytokines is limited by life threatening toxicity. Treatment with cancer vaccines is initially promising but with time the tumor usually develops immune tolerance, often by an alteration in phenotypic antigen expression to which the vaccine responds. Indeed, the four types of treatment for cancer noted above all have serious limitations: surgery (the inability to completely remove extensive metastasis), radiation (the inability to selectively deliver radiation to cancer cells), chemotherapy (the inability to selectively kill cancer cells in the presence of rapidly proliferating normal cells), and immunotherapy (noted above). For this reason, other newer therapeutic approaches are under exploration (e.g., kinase inhibitors, antiangiogenesis agents, gene therapy) but these treatments are, relatively speaking, in their infancy. Therefore, a need still exists for novel compounds (e.g., a non-cytotoxic, chemotherapeutic drug), which are efficacious (e.g., reduction of tumor size or spread of metastases) and have reduced toxicity and can be used either alone or in combination with standard chemotherapeutic drugs, for the treatment of cancers which include pancreatic cancer.
Pancreatic cancer is a malignant tumor within the pancreatic gland. The pancreatic gland, or pancreas, is a large elongated gland which lies behind the stomach. The external or exocrine secretions of the pancreas contain digestive enzymes necessary for the processing (breakdown) of food. An internal or endocrine secretion, insulin, is produced by the beta cells of the pancreas while another internal secretion, glucagon, is produced by the alpha cells of the pancreas. Insulin reduces the amount of sugar in the blood while glucagon increases blood sugar. The exocrine and endocrine cells of the pancreas form completely different types of tumors. Exocrine tumors constitute the most common type of pancreatic cancer. Although benign (non-cancerous) cysts and benign tumors (cystadenomas) can occur, most pancreatic exocrine tumors are malignant of which approximately 95% are adenocarcinomas. Patients diagnosed with pancreatic cancer typically have a poor prognosis primarily because the cancer usually causes no symptoms until metastasis of the primary tumor takes place. Median survival from diagnosis of the cancer is approximately three to six months while five-year survival is significantly less than 5%.
Treatment of pancreatic cancer depends upon the stage or extent of the disease. Radical pancreaticoduodenectomy is currently the only chance of cure, especially for minimal disease. Although chemotherapy yields some improvement in survival of patients with locally advanced disease, the overall effect is small. Also, surgery or radiotherapy of locally advanced unresectable pancreatic cancer does not lead to significantly prolonged survival. Pancreatic cancer patients have approximately a 3% chance of survival beyond one year after metastasis (e.g., first diagnosis of cancer) occurs. This rate or survival increases to 18% upon treatment with the cytotoxic drug gemcitabine (Gemzar™) and gemcitabine is the standard first line therapy for pancreatic cancer. Gemcitabine is a vicinol difluorine substituted deoxycytidine analogue which functions as an antimetabolite chemotherapeutic drug. As such, gemcitabine suffers the two significant limitations noted above for chemotherapeutic drugs in general; toxicity arising from a lack of specificity between cancer cells and rapidly dividing normal cells and the eventual development of drug resistance. More recently, approval has been given to treatment of metastatic pancreatic cancer with the combination of erlotinib (Tarceva™) and gemcitabine. However, the one-year survival for pancreatic cancer patients increases only from 18% for treatment with gemcitabine alone to 24% with combination gemcitabine and erlotinib. Erlotinib is a low molecular weight synthetic inhibitor of the epidermal growth factor receptor tyrosine kinase and so belongs to the newer class of drugs, kinase inhibitors, noted above. However, like cytotoxic drugs, the kinase inhibitors are quite toxic due to the inability to distinguish between cancer cells and rapidly dividing normal cells and they are prone to develop resistance with prolonged use.
In view of the above, there is a strong need for new approaches of cancer treatment wherein efficacy of the chemotherapeutic drug is increased and its toxicity is decreased. More particularly, there is a need for the treatment of metastatic pancreatic cancer because its prognosis is poor and the only few treatment options available include the use of highly toxic drugs which lose their efficacy with time. There is thus an urgent need for new approaches exemplified by a novel treatment regimen consisting of a novel combination of drugs yielding unanticipated efficacy (e.g., reduction in tumor size or spread of metastasis) while resulting in limited toxicity in order to provide a significant improvement in the otherwise abysmal outcome for pancreatic cancer patients.
The Applicant is aware of the followings references which may suggest a link between medium-chain length fatty acids and antitumor activity: Tolnai et al., Can. J. Biochem. Physiol. 39:713-719, 1961; Tolnai et al., Can. J. Biochem. Physiol. 40:1367-1373, 1962; Tolnai et al. Can. J. Biochem. 44:979-981, 1966; Nishikawa et al. Chem. Pharm. Bull. Tokyo 24:387-393, 1976; Burton et al. Am. J. Clin. Nutr. 53:10825-10865, 1991; U.S. Pat. No. 5,081,105; Colquhoun et al., Gen. Pharmac. 30:191-194, 1998; and Falconer et al., Br. J. Cancer 69:826-832, 1994. However it was unknown prior to the present invention that medium-chain length fatty acids, metallic salts or triglycerides thereof may be effective for the treatment of pancreatic cancer.
The present invention addresses the two limitations noted hereinabove that arise with commonly used commercial chemotherapeutic agents, i.e. drug toxicity and drug resistance by providing novel methods, compounds, and compositions for the treatment of pancreatic cancer in a human patient.
Additional features of the invention will be apparent from review of the disclosure, drawings and description of the invention below.